CN114573470A - Method for synthesizing N-trifluoroacetyl tert-leucine - Google Patents
Method for synthesizing N-trifluoroacetyl tert-leucine Download PDFInfo
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- FCTPLAZWXGEGKO-SCSAIBSYSA-N (2s)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoic acid Chemical compound CC(C)(C)[C@@H](C(O)=O)NC(=O)C(F)(F)F FCTPLAZWXGEGKO-SCSAIBSYSA-N 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 19
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 16
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims abstract description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000012074 organic phase Substances 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 13
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 16
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
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- 230000008034 disappearance Effects 0.000 description 5
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- NPDBDJFLKKQMCM-BYPYZUCNSA-N (2r)-2-azaniumyl-3,3-dimethylbutanoate Chemical compound CC(C)(C)[C@@H]([NH3+])C([O-])=O NPDBDJFLKKQMCM-BYPYZUCNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
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- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- -1 MOH inorganic base Chemical class 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing N-trifluoroacetyl tert-leucine, which is characterized by comprising the following steps: adding tertiary leucine shown in a formula (I) and methanol into a reaction container, cooling to 0-10 ℃, adding MOH solid inorganic base and a catalyst, dripping ethyl trifluoroacetate shown in a formula (II) into the solution, reacting at room temperature for 3-4 hours, concentrating reaction liquid, performing post treatment to obtain a crude product, adding toluene into the crude product, crystallizing at-5-5 ℃ for 3-6 hours, filtering, drying to obtain N-trifluoroacetyl tertiary leucine shown in a formula (III), wherein the reaction formula is as follows,
the MOH solid inorganic base is LiOH or NaOH, and the catalyst is tetrabutylammonium fluoride. The invention has mild reaction, simple operation and pure productThe degree is high.
Description
Technical Field
The invention relates to a synthetic preparation method of a drug intermediate N-trifluoroacetyl tert-leucine, belonging to the technical field of drug synthesis.
Background
N-trifluoroacetyl tert-leucine is used as an important intermediate and widely used in drug synthesis, and particularly has attracted extensive attention as a key intermediate for preparing new crown drugs. The synthesis of N-trifluoroacetyl tert-leucine mainly adopts the reaction of ethyl trifluoroacetate and tert-leucine in methanol by using organic alkali, or adopts the reaction of protected carboxyl of tert-leucine and trifluoroacetic anhydride or trifluoroacetic acid to obtain a product. In the preparation methods, compared with trifluoroacetic anhydride as an acylation reagent, the preparation of tert-leucine directly with ethyl trifluoroacetate under alkaline conditions is simpler and more convenient, and the atom economy of raw materials is improved. Dainis Dakternieks et al, in Tetrahedron Asymmetry, 2003, page 3066 and WO2004065334, report the preparation of N-trifluoroacetyl tert-leucine using triethylamine as the base; WO2021250648 and Victor W.Rosso et al, 2001, org.Pro.Res. & Dev (organic Process research and development), page 294, 298, also describe methods for the preparation of N-trifluoroacetyl-L-tert-leucine, the former uses a methanol solution of sodium methoxide as a base to synthesize the target product, N-heptane as a crystallization solvent, and the latter uses potassium methoxide as a base to prepare the target product after crystallization by adding a seed crystal, but no related crystallization method is available. The above data show no information about the purity of the product, and the price of the alkali used is relatively high.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel method for synthesizing N-trifluoroacetyl tert-leucine, MOH solid inorganic base used in the method is a common compound, is cheap and easy to obtain, the use amount of a phase transfer catalyst is small, and the purity of the obtained product is high.
In order to solve the technical problems, the invention adopts the following technical scheme: a method for synthesizing N-trifluoroacetyl tert-leucine comprises the steps of adding tert-leucine shown in a formula (I) and methanol into a reaction container, cooling to 0-10 ℃, adding MOH solid inorganic base and a catalyst, dripping ethyl trifluoroacetate shown in a formula (II) into a solution, reacting at room temperature for 3-4 hours, concentrating a reaction solution, performing aftertreatment to obtain a crude product, adding toluene into the crude product, crystallizing at-5-5 ℃ for 3-6 hours, filtering, drying to obtain N-trifluoroacetyl tert-leucine shown in a formula (III), wherein the reaction formula is as follows,
the MOH solid inorganic base is LiOH or NaOH, and the catalyst is tetrabutylammonium fluoride.
Further, the mass-volume ratio of the tert-leucine shown in the formula (I) to the methanol is 1g: 3-6 mL.
Further, the molar ratio of the tertiary leucine shown in the formula (I) to the MOH is 1: 1.05-1.3.
Further, the weight amount of the catalyst is 1-2% of the weight amount of the tert-leucine shown in the formula (I).
Further, the molar ratio of the tert-leucine shown in the formula (I) to the ethyl trifluoroacetate shown in the formula (II) is 1: 1.05-1.3.
Further, the volume mass ratio of the toluene for crystallization to the tert-leucine shown in the formula (I) is 3-8 mL: 1g of the total weight of the composition.
Further, in the post-treatment, purified water is added after the reaction solution is concentrated, the pH of the solution is adjusted by acid, extraction is carried out by ethyl acetate, the organic phase is washed by saturated salt water, and then drying, filtering and concentrating the filtrate to obtain a crude product.
Further, the acid used for adjusting the pH of the solution is hydrochloric acid or citric acid, and the pH is adjusted to 1-3.
Further, after crystallization and filtration, vacuum drying is carried out at 45 ℃ for 6 to 10 hours.
The invention has the beneficial effects that:
under the action of MOH and a small amount of phase transfer catalyst, the tertiary leucine can show good solubility in methanol, the reaction can be promoted to be effectively carried out, the reaction condition is mild, and the product shown in the formula (III) can be obtained by simply adjusting pH, extracting, concentrating, crystallizing and the like after the reaction is finished. Meanwhile, the mol price of the MOH inorganic base is obviously lower than that of common sodium methoxide or triethylamine, so that the cost can be effectively reduced. In the invention, the purity of the product shown in the formula (III) is more than 99.8%, and each impurity in the product is less than 0.1%, so that the research cost of related substances can be effectively reduced for the preparation of the new crown medicament.
Drawings
FIG. 1 is a-ESI spectrum of N-trifluoroacetyl-L-tertiary leucine represented by formula (III) in example 1;
FIG. 2 shows the preparation of N-trifluoroacetyl-L-tert-leucine of formula (III) in example 11H NMR spectrum;
FIG. 3 shows the preparation of N-trifluoroacetyl-L-tert-leucine of formula (III) in example 113C NMR spectrum;
FIG. 4 is an HPLC chromatogram of N-trifluoroacetyl-L-tertiary leucine of formula (III) of example 1;
FIG. 5 is an HPLC chromatogram of N-trifluoroacetyl-L-tertiary leucine of formula (III) in example 3;
FIG. 6 is an HPLC chromatogram of N-trifluoroacetyl-D-tertiary leucine of formula (III) in example 6.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Placing 10g L-tert-leucine (0.076mol, 1eq) in a 250mL three-necked reaction flask at room temperature, adding 30mL of methanol, stirring and cooling the solution in ice bath to 8 ℃, adding 0.2g of tetrabutylammonium fluoride and 3.3g of sodium hydroxide (0.085mol, 1.12eq), stirring at the same temperature for 10 minutes, adding 11.4g (0.08mol, 1.05eq) of ethyl trifluoroacetate to the solution, reacting at 18 ℃ for 4 hours, detecting the substantial disappearance of raw materials by TLC (n-butanol: acetic acid: water: 4:1:1), concentrating the solution, adding 30mL of purified water to the concentrated residue, adjusting the pH of the solution to 3 with 15% hydrochloric acid, extracting with ethyl acetate for 3 times, 30mL each time, combining the organic phases, washing with saturated common salt water for 2 times, 100mL each time, separating the organic phase, drying anhydrous sodium sulfate, filtering, concentrating to obtain a viscous substance, adding 50mL of toluene, stirring and crystallizing at 3 ℃ for 3 hours, filtering, leaching the solid with ice toluene for 2 times, each time 10mL, and vacuum drying at 45 ℃ for 6 hours to obtain 14.7g of white powder solid with yield of 84.9%, and carrying out structural identification, ESI-: [ M-1 ]]226 (see figure 1 of the drawings),1H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，9.41(d，J＝5.4Hz，1H)，4.21(d，J＝5.1hz, 1H),1.0(s, 9H) (see figure 2),13C NMR(300MHz，DMSO-d6)δ171.36，156.74(q，2JCF)，112.9(q，1JCF) 61.56, 34.1, 27.05 (see FIG. 3), MS and NMR results were consistent with theory, HPLC purity 99.85% (see FIG. 4), single impurity less than 0.1%.
Example 2
20g (0.152mol, 1.0eq) of D-tert-leucine was placed in a 250mL three-necked reaction flask at room temperature, 120mL of methanol was added, the solution was cooled to 10 ℃ with stirring and ice-cooling, 0.3g (1.5% by weight of D-tert-leucine) of tetrabutylammonium fluoride and 4.72g of lithium hydroxide (0.197mol, 1.3eq) were added, stirred at the same temperature for 10 minutes, ethyl trifluoroacetate 28.2(0.198mol,1.3eq) was added to the solution, the reaction was carried out at 15 ℃ for 4 hours, TLC (n-butanol: acetic acid: water 4:1:1) was used to detect the substantial disappearance of the starting materials, the solution was concentrated, 30mL of purified water was added to the concentrated residue, the pH of the solution was adjusted to 3 with 10% of citric acid, extraction was carried out with ethyl acetate 3 times, 30mL each time, the organic phases were combined, washed with saturated common salt 2 times, 100mL each time, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a viscous substance, adding 60mL of toluene, stirring at 0 ℃ for crystallization for 5 hours, filtering, leaching the solid with ice toluene for 2 times, each time 10mL, and vacuum drying at 45 ℃ for 6 hours to obtain 29.6g of white powder solid, wherein the yield is 85.5%, the HPLC purity is 99.85%, and the single impurity content is less than 0.1%.
Example 3
Placing 100g L-tert-leucine (0.762mol, 1.0eq) into a 1000mL three-neck reaction flask at 10 ℃, adding 400mL methanol, stirring and cooling the solution to 5 ℃ in an ice bath, adding 2.0g (2% by weight of L-tert-leucine) of tetrabutylammonium fluoride and sodium hydroxide (35.1g,0.8775mol, 1.15eq), stirring at the same temperature for 20 minutes, adding 116.9g (0.83mol, 1.08eq) of ethyl trifluoroacetate dropwise into the solution, heating the solution to 15 ℃, reacting for 3.5 hours, detecting the substantial disappearance of the raw materials by TLC (n-butanol: acetic acid: water: 4:1:1), concentrating the solution, adding 200mL purified water to the residue, adjusting the pH of the solution to 2 with 20% hydrochloric acid, extracting with ethyl acetate for 3 times, 300mL for the first time, 150mL for the second time, combining organic phases with common salt, washing 2 times with saturated water, 200mL each time, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain colorless viscous substance, adding 400mL toluene, stirring at 5 deg.C for crystallizing for 6 hr, filtering, rinsing the solid with ice toluene for 3 times (30 mL each time), and vacuum drying at 45 deg.C for 7 hr to obtain white powder solid 132.6g, yield 76.5%, and HPLC purity 99.9% (see figure 5).
Example 4
At room temperature, 50g L-tert-leucine (0.381mol, 1.0eq) was placed in a 500mL three-necked reaction flask, 250mL of methanol was added, the solution was cooled to 5 ℃ with stirring and ice-cooling, 0.5g (1% by weight of L-tert-leucine) of tetrabutylammonium fluoride and 17.5g of sodium hydroxide (0.4375mol, 1.15eq) were added, stirred at the same temperature for 20 minutes, ethyl trifluoroacetate (62.2g, 0.438mol, 1.15eq) was added to the solution, the reaction was carried out at 10 ℃ for 4 hours, TLC (n-butanol: acetic acid: water 4:1:1) was detected that the starting material had substantially disappeared completely, the solution was concentrated, 200mL of purified water was added to the concentrated residue, the pH of the solution was adjusted to 3 with 10% citric acid, extraction was carried out with ethyl acetate 3 times, 150mL each time, the organic phases were combined, washed with 2 times of saturated common salt, 300mL each time, the organic phase was separated out, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a viscous substance, adding 400mL of toluene, stirring at-5 ℃ for crystallization for 4 hours, filtering, leaching the solid with ice toluene for 2 times, each time 30mL, and vacuum drying at 45 ℃ for 8 hours to obtain 71g of white powder solid with the yield of 82%, the HPLC purity of 99.84% and the single impurity content of less than 0.1%.
Example 5
Placing 300g L-tert-leucine (2.29mol, 1.0eq) in a 3000mL three-necked reaction flask at room temperature, adding 1200mL of methanol, stirring and cooling the solution in an ice bath to 5 ℃, adding 5g (1.7% by weight of L-tert-leucine) of tetrabutylammonium fluoride and 100g of sodium hydroxide (2.5mol, 1.1eq), stirring at the same temperature for 30 minutes, adding ethyl trifluoroacetate (374g, 2.63mol, 1.15eq) to the solution, reacting at 26 ℃ for 3.5 hours, detecting the substantial disappearance of the raw materials by TLC (n-butanol: acetic acid: water: 4:1:1), concentrating the solution, adding 700mL of purified water to the concentrated residue, adjusting the pH of the solution to 2 with 20% hydrochloric acid, extracting 2 times with ethyl acetate, 500mL for the first time, 300mL for the second time, combining the organic phases, washing the organic phases with 2 times of saturated common salt, 500mL each time, separating the organic phase with sodium sulfate, drying the anhydrous sodium sulfate, filtering, concentrating to obtain a viscous substance, adding 1200mL of toluene, stirring at-2 ℃ for crystallization for 6 hours, filtering, rinsing the solid with ice toluene for 3 times, 50mL each time, and vacuum-drying at 45 ℃ for 10 hours to obtain 432.4g of white powder solid, wherein the yield is 83.2%, the HPLC purity is 99.8%, and the single impurity content is less than 0.1%.
Example 6
Placing 100g D-tert-leucine (0.762mol, 1.0eq) in a 1000mL three-neck reaction flask at room temperature, adding 600mL of methanol, stirring and cooling the solution in ice bath to 3 ℃, adding 1.5g (1.5% by weight of D-tert-leucine) of tetrabutylammonium fluoride and 21.8g of lithium hydroxide (0.91mol, 1.2eq), stirring at the same temperature for 20 minutes, adding ethyl trifluoroacetate (119g, 0.84mol, 1.1eq) to the solution, reacting at 30 ℃ for 4 hours, detecting the substantial disappearance of the raw materials by TLC (n-butanol: acetic acid: water: 4:1:1), concentrating the solution, adding 300mL of purified water to the concentrated residue, adjusting the pH of the solution to 3 with phosphoric acid, extracting with ethyl acetate 3 times, 200mL each time, combining the organic phases, washing with saturated common salt for 2 times, 300mL each time, separating the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a viscous substance, adding 800mL toluene, stirring at-5 deg.C for crystallization for 4 hr, filtering, rinsing the solid with ice toluene 3 times (30 mL each time), vacuum drying at 45 deg.C for 8 hr to obtain white powder solid 140.7g, yield 81.2%, and HPLC purity 99.80% (see figure 6).
In the preparation process, n-hexane, cyclohexane, ethyl acetate and the like and mixtures thereof are used for crystallizing the obtained crude product, but the yield is low, the crystallization is difficult, and seed crystals are required to be added. The invention adopts toluene for crystallization at low temperature, and has the advantages of easy crystallization, simple operation and good purity repeatability.
Claims (8)
1. A method for synthesizing N-trifluoroacetyl tert-leucine is characterized by comprising the following steps: adding tertiary leucine shown in a formula (I) and methanol into a reaction container, cooling to 0-10 ℃, adding MOH solid inorganic base and a catalyst, dripping ethyl trifluoroacetate shown in a formula (II) into the solution, reacting at room temperature for 3-4 hours, concentrating reaction liquid, performing post treatment to obtain a crude product, adding toluene into the crude product, crystallizing at-5-5 ℃ for 3-6 hours, filtering, drying to obtain N-trifluoroacetyl tertiary leucine shown in a formula (III), wherein the reaction formula is as follows,
the MOH solid inorganic base is LiOH or NaOH, and the catalyst is tetrabutylammonium fluoride.
2. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: the mass-volume ratio of the tert-leucine shown in the formula (I) to the methanol is 1g: 3-6 mL.
3. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: the molar ratio of the tert-leucine to MOH shown in the formula (I) is 1: 1.05-1.3.
4. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: the weight amount of the catalyst is 1-2% of the weight amount of the tert-leucine shown in the formula (I).
5. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: the molar ratio of the tert-leucine shown in the formula (I) to the ethyl trifluoroacetate shown in the formula (II) is 1: 1.05-1.3.
6. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: the volume mass ratio of toluene for crystallization to tert-leucine shown in formula (I) is 3-8 mL: 1g of the total weight of the composition.
7. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 1, wherein: in the post-treatment, purified water is added after reaction liquid is concentrated, the pH value of the solution is adjusted by acid, then ethyl acetate is used for extraction, an organic phase is washed by saturated salt water, and then drying and filtering are carried out, and a crude product is obtained by concentrating filtrate.
8. The method for synthesizing N-trifluoroacetyl tert-leucine according to claim 7, wherein: the acid used for adjusting the pH of the solution is hydrochloric acid or citric acid, and the pH is adjusted to 1-3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105335A1 (en) * | 2000-03-03 | 2003-06-05 | Stefan Hildrand | Method for producing beta-alaninamides |
| WO2021250648A1 (en) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| CN114031543A (en) * | 2021-12-21 | 2022-02-11 | 上海朴颐化学科技有限公司 | Preparation method of intermediate of palovaried |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105335A1 (en) * | 2000-03-03 | 2003-06-05 | Stefan Hildrand | Method for producing beta-alaninamides |
| WO2021250648A1 (en) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| CN114031543A (en) * | 2021-12-21 | 2022-02-11 | 上海朴颐化学科技有限公司 | Preparation method of intermediate of palovaried |
Non-Patent Citations (1)
| Title |
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| MATTHEW R. HICKEY等: "Trifluoroacetylation of Amino Acids under Aqueous Conditions Using a Readily Prepared Non-Odoriferous Reagent", SYNLETT * |
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Address after: 317016 coastal industrial zone, Taizhou, Zhejiang, China Patentee after: Zhejiang Haizhou Pharmaceutical Co.,Ltd. Address before: 317016 coastal industrial zone, Taizhou, Zhejiang, China Patentee before: ZHEJIANG HAIZHOU PHARMACEUTICAL CO.,LTD. |